Circulating level of α2-macroglobulin–β2-microglobulin complex in hemodialysis patients

Motomiya, Yoshihiro; Ando, Yumiko; Haraoka, Katsuki; Sun, Xuguo; Iwamoto, Hisahiko; Uchimura, Tomonori; Maruyama, Ikuro

doi:10.1046/j.1523-1755.2003.00315.x

Cited by 25 publications

(26 citation statements)

References 27 publications

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“…The binding of Leu-Ile or FK506 for Hsc70 was examined by quartz crystal microbalance (QCM), which is useful for studying mass-measuring and molecular interaction in aqueous solutions (Motomiya et al, 2003). Briefly, 100 l of each dipeptide (10 g/ml in PBS) or FK506 [10 g/ml in chloroform or chloroform/ethanol (1:1)] was immobilized into a QCM plate for 1 h at room temperature, and then removed.…”

Section: Methodsmentioning

confidence: 99%

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

Cen¹,

Nitta²,

Ohya³

et al. 2006

J. Neurosci.

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Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor that has therapeutic implications for neurodegenerative disorders. We previously showed that leucine-isoleucine (Leu-Ile), an analog of a dipeptide-like structure of FK506 (tacrolimus), induces GDNF expression both in vivo and in vitro. In this investigation, we sought to clarify the cellular mechanisms underlying the GDNF-inducing effect of this dipeptide. Leu-Ile transport was investigated using fluorescein isothiocyanate-Leu-Ile in cultured neurons, and the results showed the transmembrane mobility of this dipeptide. By liquid chromatography-mass spectrometry and quartz crystal microbalance assay, we identified heat shock cognate protein 70 as a protein binding specifically to Leu-Ile, and molecular modeling showed that the ATPase domain is the predicted binding site. Leu-Ile stimulated Akt phosphorylation, which was attenuated significantly by heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA). Moreover, enhanced interaction between phosphorylated Akt and Hsp90 was detected by immunoprecipitation. Leu-Ile elicited an increase in cAMP response element binding protein (CREB) phosphorylation, which was inhibited by GA, indicating that CREB is a downstream target of Hsp90/Akt signaling. Leu-Ile elevated the levels of GDNF mRNA and protein expression, whereas inhibition of CREB blocked such effects. Leu-Ile promoted the binding activity of phosphorylated CREB with cAMP response element. These findings show that CREB plays a key role in transcriptional regulation of GDNF expression induced by Leu-Ile. In conclusion, Leu-Ile activates Hsp90/Akt/CREB signaling, which contributes to the upregulation of GDNF expression. It may represent a novel lead compound for the treatment of dopaminergic neurons or motoneuron diseases.

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Section: Methodsmentioning

confidence: 99%

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

Cen¹,

Nitta²,

Ohya³

et al. 2006

J. Neurosci.

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“…Aside from its interactions with proteases, α 2 M binds to Aβ peptide and β 2 -microglobulin, which are associated with Alzheimer's disease (Narita et al, 1997) and dialysis related amyloidosis (Motomiya et al, 2003), respectively, to cytokines and growth factors (Mettenburg et al, 2002), and to a range of hydrophobic molecules including endotoxin, phenyl-Sepharose, and liposomes (Barrett 1981). The binding to hydrophobic molecules does not inhibit the trapping of proteases and is not known to be associated with any conformational changes (Barrett 1981).…”

Section: Haptoglobinmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…Examples of ligands include A␤ (15), prion protein (16) and ␤ 2 -microglobulin (17), which are strongly linked with Alzheimer disease, the spongiform encephalopathies, and dialysis-related amyloidosis, respectively. In addition, ␣ 2 M binds to cytokines and growth factors (18) and to a range of hydrophobic structures including endotoxin, phenyl-Sepharose, and liposomes (19).…”

mentioning

confidence: 99%

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

Yerbury

Kumita

Meehan

et al. 2009

Journal of Biological Chemistry

110

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␣ 2 -Macroglobulin (␣ 2 M) and haptoglobin (Hp) are both abundant secreted glycoproteins that are best known for their protease trapping and hemoglobin binding activities, respectively. Like the small heat shock proteins, both these glycoproteins have in common the ability to protect a range of proteins from stress-induced amorphous aggregation and have been described as extracellular chaperones. Using an array of biophysical techniques, this study establishes that in vitro at substoichiometric levels and under physiological conditions ␣ 2 M and Hp both inhibit the formation of amyloid fibrils from a range of proteins. We also provide evidence that both ␣ 2 M and Hp interact with prefibrillar species to maintain the solubility of amyloidogenic proteins. These findings suggest that both ␣ 2 M and Hp are likely to play an important role in controlling the inappropriate aggregation of proteins in the extracellular environment.

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Circulating level of α2-macroglobulin–β2-microglobulin complex in hemodialysis patients

Cited by 25 publications

References 27 publications

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

Extracellular Chaperones and Amyloids

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

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